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ALK-positive Non-small Cell Lung Cancer (NSCLC)Phase 1/2NCT03131206

A Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid Cancer

A Phase 1/2 study testing Alectinib in people with ALK-positive Non-small Cell Lung Cancer (NSCLC) and RET-positive Non-small Cell Lung Cancer (NSCLC), run by Dana-Farber Cancer Institute at 4 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This research trial is studying a drug called alectinib as a possible treatment for non-small cell lung cancer (NSCLC) with specific genetic alterations known as ALK or RET rearrangements, and thyroid cancer with RET rearrangements. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Alectinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
4 sitesUnited States
Study dates
19 Jun 2017to 8 Apr 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Tumor Types:
  • Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis of locally advanced (AJCC Stage IIIB) not amenable to curative therapy or metastatic (AJCC Stage IV) NSCLC that carries a RET rearrangement, as determined by fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or next generation sequencing (NGS) via a CLIA-certified local diagnostic test (LDT).
  • --- OR-
  • Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis of metastatic (AJCC Stage IV) NSCLC that carries an ALK rearrangement with CNS metastases, as determined by FISH, RT-PCR, immunohistochemistry (IHC), or NGS via a CLIA-certified LDT.
  • Phase 2 Cohorts A\&B: Subjects must have a histologically or cytologically confirmed diagnosis of locally advanced (AJCC Stage IIIB) not amenable to curative therapy or metastatic (AJCC Stage IV) NSCLC that carries a RET rearrangement, as determined by FISH, RT-PCR, or NGS via a CLIA-certified LDT.
  • Phase 2 Cohort C (thyroid cancer): Subjects must have a histologically or cytologically confirmed diagnosis of metastatic thyroid cancer (Stage IV) that carries either a RET rearrangement or activating RET mutation, as determined by FISH, RT-PCR, or NGS via a CLIA-certified LDT.
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  • Disease Status Requirements:
  • Phase 1: Subjects with a RET rearrangement must have had disease progression after at least one prior line of systemic therapy. Subjects with an ALK rearrangement may be either treatment naive or may have received prior treatment, and must have CNS disease present at baseline. Subjects cannot have received more than one prior RET TKI (such as, but not limited to, vandetanib, sorafenib, sunitinib, ponatinib, or cabozantinib). Subjects enrolling to the Phase 1 portion of the trial must not have received prior alectinib therapy.
  • Phase 2:
  • Cohort A: RET-positive NSCLC subjects must have received at least one prior line of therapy, but must be RET TKI-naive.
  • Cohort B: RET-positive NSCLC that has previously been treated with one RET TKI. Subjects cannot have received more than one prior RET TKI and must not have received prior alectinib.
  • Cohort C: RET-positive thyroid cancer, must be radioactive iodine refractory.
  • Subjects must have at least one measurable target lesion according to RECIST v1.1.
  • Subjects enrolling to the phase 1 portion of the trial who have received a prior RET TKI must be able and willing to undergo a pre-treatment fresh tumor biopsy.
  • Subjects enrolling to Cohort B or C of the phase 2 portion of the trial who have received a prior RET TKI must be able and willing to undergo a pre-treatment fresh tumor biopsy.
  • All subjects must have archival tissue confirmed as available for enrollment. Subjects who are TKI naive who do not have archival tissue may undergo a fresh tumor biopsy in lieu of the archival tissue requirement. The archival tissue requirement may be waived for subjects after discussion with the principal investigator.
  • Age ≥ 18 years.
  • ECOG performance status ≤2 (See APPENDIX A)
  • Subjects must have normal organ and marrow function as defined below:
  • Adequate hematologic function
  • Absolute neutrophil count ≥1,500/mcL
  • Platelets ≥100,000/mcL
  • Hemoglobin ≥ 9.0 g/dL -- Adequate renal function
  • serum creatinine ≤1.5 x institutional ULN
  • ---- OR-
  • Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 as calculated using the Modification of Diet Renal Disease Equation (See APPENDIX B)
  • Subjects must have recovered from treatment toxicities to ≤ Grade 1 or to their pretreatment levels. Subjects who have developed interstitial lung disease (ILD) must have fully recovered.
  • For all females of childbearing potential, a negative serum pregnancy test must be obtained within 3 days prior to starting study treatment.
  • For women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study drug. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods) and withdrawal are not acceptable methods of contraception. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices.
  • For men: agreement to remain abstinent or use a contraceptive method that results in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study drug. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • Cytotoxic chemotherapy or immunotherapy within 3 weeks of study entry.
  • Oral targeted therapy within 5 half-lives (if known) or 3 weeks (if half-life is unknown) of study entry.
  • Phase 1: subjects who have received prior alectinib therapy.
  • For enrollment to the phase 1 portion of the trial: Administration of any cytochrome P450 (CYP)3A inhibitors or inducers within 14 days prior to the first dose of alectinib and from Cycle 1 Day 1 - Cycle 2 Day 8 of the phase 1 portion of the trial. Following completion of this period, strong/potent cytochrome P450 (CYP)3A inhibitors or inducers are prohibited while on study. Please see APPENDIX C.
  • Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have completed at least 2 weeks prior to study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry.
  • Major surgery within 4 weeks of study entry. Minor surgical procedures (e.g., port insertion) are not excluded, but sufficient time should have passed for wound healing (as determined by the treating investigator).
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  • Subjects who are receiving any other investigational agents.
  • Liver disease characterized by:
  • -- ALT or AST > 3 × institutional ULN (≥ 5 × ULN for subjects with concurrent liver metastasis) confirmed on two consecutive measurements
  • --- OR-
  • Absolute impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices
  • --- OR-
  • Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices
  • ---OR-
  • Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis
  • Subjects with symptomatic CNS metastases who are neurologically unstable and/or require an increased dose of steroid to manage CNS symptoms within 1 week prior to the first day of treatment are excluded.
  • Subjects with brain or leptomeningeal metastases that do not meet the above criteria are allowed.
  • Symptomatic disease is allowed as long as symptoms are controlled and stable.
  • History of hypersensitivity to any of the additives in the alectinib drug formulation.
  • Subjects with symptomatic bradycardia.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant or breastfeeding women.
  • Any GI disorder that may affect absorption of oral medications in the opinion of the treating investigator, such as malabsorption syndrome or major bowel or stomach resection.
  • Subjects who are unable to swallow pills.
  • Subjects with a history of a second primary malignancy. Exceptions include: subjects with a history of malignancies that were treated curatively and have not recurred within 3 years prior to study entry; resected basal and squamous cell carcinomas of the skin, and completely resected carcinoma in situ of any type.
  • NCI-CTCAE v4.03 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication.
  • Known HIV positivity or AIDS-related illness.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02115

  • Brigham and Women's Hospital

    Boston, Massachusetts, 02115

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • University of California, Irvine

    Irvine, California, 92697-7600

Other trials in United States

About this study

Official title: A Phase 1/2 Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid Cancer

This research trial is studying a drug called alectinib as a possible treatment for non-small cell lung cancer (NSCLC) with specific genetic alterations known as ALK or RET rearrangements, and thyroid cancer with RET rearrangements.

Read the detailed description

This is a Phase I/II research study, which means that researchers are testing different doses of the drug alectinib in participants with cancer to evaluate its safety, determine a safe dosage range, and identify side effects.

The FDA (the U.S. Food and Drug Administration) has approved alectinib as a treatment option for NSCLC, but at a different dosage.

There are two parts to this study, Phase 1 and Phase 2. In Phase 1, patients with ALK or RET rearranged NSCLC will receive different doses of alectinib to determine the highest dose that can be administered without severe or unmanageable side effects. This is called the maximum tolerated dose and will be the recommended dose for the next part of the study, Phase 2. A Phase I clinical trial tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

During Phase 2, participants with RET rearranged NSCLC or thyroid cancer will be given the maximum tolerated dose. During both Phase 1 and Phase 2, the investigators will determine the effect alectinib has on the body, and the effect alectinib has on cancer.

Alectinib belongs to a class of drugs known as tyrosine kinase inhibitors, which stop tyrosine kinases from working. Tyrosine kinases are enzymes that are responsible for activating many proteins in the body's cells. The ALK and RET kinases play an important role in the survival and growth of tumor cells and in the ability of tumor cells to spread to different parts of the body. In laboratory studies and in patients, alectinib has been shown to block the ALK and RET kinases. By blocking these kinases and stopping them from working, it is hoped that alectinib may prevent the survival of tumor cells in addition to stopping their growth and ability to spread.

The purpose of this research study is to learn about the effects of the study drug alectinib, and to find the best dose for treating ALK-positive or RET-positive cancers.

Being tested
Alectinib
Keywords
Non-small cell lung cancer, NSCLC, ALK, RET, alectinib, Thyroid cancer
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Thyroid Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AlectinibDrug

    Also called Alecensa

    • Oral, BID
    • Phase I: A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
    • Phase II: Participants will be treated at the RP2D identified during Phase I. Each treatment cycle will be defined as 28 consecutive days.
Study groups in NCT03131206
Study groupRoleWhat they receive
Phase 1 RP2D of alectinibExperimentalThe investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have NSCLC, not everyone who participates in this research study will receive the same dose of the study drug. The dosage will depend on the number of participants who have been enrolled in the study and how well the dosage has been tolerated. * Alectinib * Oral, BID * A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
Receives: Drug: Alectinib
Cohort AExperimentalParticipants with RET-rearranged NSCLC with no previous history of RET-TKI therapy. * Alectinib * Oral, BID, participants will receive the RP2D identified during Phase 1. * Each treatment cycle will be defined as 28 consecutive days.
Receives: Drug: Alectinib
Cohort BExperimentalParticipants with RET-rearranged NSCLC with previous history of RET-TKI therapy. * Alectinib * Oral, BID, participants will receive the RP2D identified during Phase 1. * Each treatment cycle will be defined as 28 consecutive days.
Receives: Drug: Alectinib
Cohort CExperimentalParticipants with RET-rearranged thyroid cancer * Alectinib * Oral, BID, participants will receive the RP2D identified during Phase 1. * Each treatment cycle will be defined as 28 consecutive days.
Receives: Drug: Alectinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (Phase 1)

    The maximally administered dose (MAD) of the study medication will be defined as the dose level where at least two subjects develop toxicities consistent with a DLT definition. In this situation, the dose level immediately below the MAD will be defined as the MTD.

    Measured: 28 Days

  2. Objective Response Rate

    Preliminary evaluation of objective response rate (ORR) of alectinib was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    Measured: 8 weeks

Secondary outcomes (5)

  1. Area Under the Plasma Concentration Versus Time Curve (AUC) of Alectinib

    AUC pharmacokinetic parameters will be estimated using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

    Results are incomplete because study closed to accrual early.

    Measured: 4 months

  2. Progression Free Survival

    Progression evaluated using RECIST 1.1 Criteria. Results are incomplete because study closed to accrual early.

    Measured: 2 Years

  3. Overall Survival

    Overall survival is recorded from start of enrollment through study completion.

    Measured: OS was calculated at the time of analysis, which was approximately 22 months after the study opened to enrollment.

  4. Duration of Response

    Response evaluated using RECIST 1.1 Criteria. Results are incomplete because study closed to accrual early.

    Measured: 2 Years

  5. Peak Plasma Concentration (Cmax) of Alectinib

    Cmax pharmacokinetic parameters will be estimated using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. Results are incomplete because study closed to accrual early.

    Measured: 4 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Apr 2017
  2. Study start19 Jun 2017
  3. Primary completion8 Nov 2018
  4. Study completion8 Apr 2019

Why it stopped: Study closed due to slow accrual and lack of efficacy.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03131206
Sponsor's protocol ID
17-080
Status last verified
Aug 2021
First submitted
19 Apr 2017
Last updated
27 Sep 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Alectinib in people with ALK-positive Non-small Cell Lung Cancer (NSCLC) and RET-positive Non-small Cell Lung Cancer (NSCLC), run by Dana-Farber Cancer Institute at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 27 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Nov 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (Phase 1) (time frame: 28 Days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03131206.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Sep 2021.

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